In the next 5 years I plan to study in vitro and in vivo the interactions of microglia, macrophages, substance P and nitric oxide as well as the effect of these substances on mitochondrial function. Substance P (SP) has effects as a pain mediator in the spinal cord and has vasoactive properties. It also plays a significant role in the pathogenesis of neurogenic inflammation, being released from peripheral nerve terminals and causing precapillary vasodilatation, postcapillary plasma extravasation and histamine release. Nitric oxide (NO) is known to play a role in bacterial meningitis and also has immunomodulatory and vasoactive properties. Peripheral blood macrophages and central nervous system (CNS) microglia share similar immunogenic properties and may be derived from the same cell line. Microglia are suspected to play a role in the pathophysiology of a wide variety of inflammatory CNS diseases and the mediators for this microglial induced injury may be modulators such as substance P and nitric oxide. The underlying hypothesis which provides the framework for all of the proposed studies is that substance P (SP), nitric oxide(NO) and microglia play a central role in the pathophysiology of bacterial meningitis (BM) and other acute CNS inflammatory conditions. The overall goal of this application is to investigate the effects of SP and NO on macrophage and microglia functions in in vitro and in vivo systems. This overall goal will be approached by addressing the following specific hypotheses. Hypothesis 1: Substance P plays a central role in bacterial meningitis, both through its direct immunomodulatory effects and through its effects on nitric oxide. In stimulated phagocytic cells there is an upregulation of preprotachykinin and SP receptor message. Hypothesis 2: Nitric oxide plays a central role in the pathophysiology of bacterial meningitis. There is upregulation of inducible nitric oxide synthase (iNOS) message resulting in increased production of NO. SP modulates iNOS via inhibition of iNOS message. Hypothesis 3: Both the resident and transient phagocytic cells in the CNS (microglia and macrophages) participate in the pathophysiology of bacterial meningitis. SP and NO modulate their effects in CNS inflammation via these cells. Hypothesis 4: The ultimate site for the effects of SP and NO may be the mitochondrial respiratory chain enzymes of these phagocytic cells.